More widespread reports of complete tumor responses to cell therapies are paralleled by increasing clinical, scientific and public interest in, therapies that can produce antitumor effects without the devastating consequences of standard chemo-radiotherapies. However, much remains to be achieved before these eariy phase therapies become a standard of clinical practice. During our prior SPORE funding , we demonstrated, that EBV antigen-specific T cells produced over 60% complete remission rate without toxicity, in 21 patients with relapsed EBV-positive lymphoma. Our complex T cell generation process was, however, identified as a critical regulatory barrier to the progress of this study to pivotal clinical studies and a biologies licensing application (BLA). The manufacturing process required live virus (EBV) and (adeno)viral vectors, as well as B cells for the generation of autologous antigen-presenting cells (APCs) - a severe limitation now that most patients receive the B cell depleting antibody rituxan upon diagnosis. We therefore developed a strategy for the production of EBV-specific T cells that does not require live virus or viral vectors and reduces both complexity and the manufacturing time (from >3 riionths to <4 weeks); increases the number of viral tumor antigens recognized from 2 to 4; and is effective for any patient regardless of HLA type or prior treatment with rituxan. In the current application, we plan a phase 1 trial to validate the biological and clinical equivalency of T cells made with the new manufacturing strategies, which will enable us to proceed to a pivotal trial (outside the scope of the SPORE) and then a BLA. In the second part of our proposal, we plan to further improve upon our 60% CR rate in relapsed disease, by combining ithe tumor-directed T cells with small molecule histone deacetylase inhibitors (HDAC-ls). These drugs have both direct anti-lymphoma activity and multiple proimmune effects that should increase the efficacy of tumor-specific T cells. Since HDAC-ls can also inhibit T cells, we will use mouse lymphoma models to evaluate how HDAC-ls and adoptive T cell transfer can best be used in combination, by identifying the mechanisms of tumor immuneresistance that can be effectively altered by HDAC-I to augment T cell persistence, proliferation and antitumor activity.